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Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are enzyme inhibitors that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4) and are a potent treatment for type 2 diabetes. Inhibition of the DPP-4 enzyme prolongs and enhances the activity of incretins that play an important role in insulin secretion and blood glucose control regulation. Type 2 diabetes is a chronic metabolic disease that can be caused by pancreas β-cell dysfunction, deficiency in insulin secretion, insulin resistance and/or increased hepatic glucose production. It is one of the fastest growing health concerns in the world. Current treatments are often inefficient at sustaining glycemic control and may cause undesirable side effects, such as weight gain and episodes of hypoglycemia. Therefore, new and more effective drugs have been developed with DPP-4 inhibitors playing a significant role. ==History== Since its discovery in 1967, serine protease DPP-4 has been a popular subject of research.〔 Inhibitors of DPP-4 have long been sought as tools to elucidate the functional significance of the enzyme. The first inhibitors were characterized in the late 1980s and 1990s. Each inhibitor was important to establish an early structure activity relationship (SAR) for subsequent investigation. It should be noted that the inhibitors fall into two main classes, those that interact covalently with DPP-4 and those that do not.〔 DPP-4 is a dipeptidase that selectively binds substrates that contain proline at the P1-position, thus many DPP-4 inhibitors have 5-membered heterocyclic rings that mimic proline, e.g. pyrrolidine, cyanopyrrolidine, thiazolidine and cyanothiazolidine.〔 These compounds commonly form covalent bonds to the catalytic residue Ser630.〔 In 1994, researchers from Zeria Pharmaceuticals unveiled cyanopyrrolidines with a nitrile function group that was assumed to form an imidate with the catalytic serine. Concurrently other DPP-4 inhibitors without a nitrile group were published but they contained other serine-interacting motifs, e.g. boronic acids, phosphonates or diacyl hydroxylamines. These compounds were not as potent because of the similarity of DPP-4 and prolyl oligopeptidase (PEP) and also suffered from chemical instability. Ferring Pharmaceuticals filed for patent on two cyanopyrrolidine DPP-4 inhibitors, which they published in 1995. These compounds had excellent potency and improved chemical stability. In 1995, Edwin B. Villhauer at Novartis started to explore N-substituted glycinyl-cyanopyrrolidines based on the fact that DPP-4 identifies N-methylglycine as a N-terminal amino acid. This group of new cyanopyrrolidines became extremely popular field of research in the following years. Some trials with dual inhibitors of DPP-4 and vasopeptidase have been represented, since vasopeptidase inhibition is believed to enhance the antidiabetic effect of DPP-4 inhibition by stimulating insulin secretion. Vasopeptidase-inhibiting motif is connected to the DPP-4 inhibitor at the N-substituent. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Development of dipeptidyl peptidase-4 inhibitors」の詳細全文を読む スポンサード リンク
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